Background: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, intensive (targeting an HbA1c ≤ 6.5%) compared to standard glucose control reduced the risk of nephropathy in patients with type 2 diabetes but did not reduce the risks of death or major macrovascular events. We report post-trial follow-up to determine whether in-trial effects were sustained or new long-term benefits emerged for major outcomes.

Methods: Surviving patients previously assigned to intensive or standard glucose control were invited to post-trial follow-up.  The primary endpoints were death from any cause and major macrovascular events. Secondary endpoints included major clinical microvascular events and requirement for renal replacement therapy.

Results: Of 11,140 originally randomized, 8494 patients were followed post-trial for a median of 5.4 years. In-trial differences in mean HbA1c levels between treatment groups were lost by the first post-randomisation visit after 2.9 years. There was no reduction in cumulative risk of death from any cause (hazard ratio (HR), intensive versus standard control =1.00; 95%CI 0.92, 1.08), major macrovascular events (1.00; 0.92, 1.08) or major clinical microvascular events (0.92; 0.80, 1.05). By contrast, the cumulative risk of requirement for renal replacement therapy was significantly reduced in the intensive versus standard control group (0.54; 0.34, 0.85).

Conclusion: Post-trial follow-up of ADVANCE participants provides no evidence that in-trial differences in glucose control produced long-term benefits on mortality or major macrovascular events. The significant in-trial benefits on end-stage renal disease remained evident at the end of follow-up.